Sulfanilamidopyrimidinylsulfonamides

ABSTRACT

N - METHYLALKANESULFONAMIDO-SUBSTITUTED SULFANILAMIDO PYRIMIDINES AND THE PHARMACEUTICALLY ACCEPTABLE METAL SALTS THEREOF ARE USEFUL AS SHORT-ACTING ANTIBACTERIAL AGENTS HAVING A LOW HYPERSENSITIVITY LIABILITY.

United States Patent Office 3,567,715 SULFANILAMIDOPYRIMIDINYLSULFONAMIDES Aubrey A. Larsen, Frederick A. Grunwald, and William E. Kreighbaum, Evansville, Ind., assignors to Mead Johnson & Company, Evansville, Ind.

No Drawing. Filed Apr. 14, 1969, Ser. No. 816,037 Int. Cl. A61k 27/00; C07d 51/44 US. Cl. 260-23955 7 Claims ABSTRACT OF THE DISCLOSURE N methylalkanesulfonamido-substituted sulfanilamide pyrimidines and the pharmaceutically acceptable metal salts thereof are useful as short-acting antibacterial agents having a low hypersensitivity liability.

This invention relates to a new class of compounds Which may be utilized in the therapeutic treatment of mammalian infections caused by microorganisms. These therapeutic agents are N-mcthyl-N-(6-sulfanilamido-4- pyrimidinyl) alkanesulfonamides and N-methyl-N-(2 sulfanilamido-S-pyrimidinyl)alkanesulfonamide of Formula I and II respectively and the pharmaceutically acceptable salts thereof. In Formula I and Formula II R is a lower alkyl group of 3 to carbon atoms. This invention also embodies processes for the preparation of these useful substances.

Formula I Da N on.

Formula II The N methyl N (sulfanilamidopyrimidinyl) alkanesulfonamides of this invention have utility as short-acting antibacterial agents. The compounds of this invention have very low toxicities and are especially suited for oral administration. ALD values are in exess of 1500 mg./kg. body weight. The compounds have lipid solubility and are rapidly absorbed from the stomach providing maximum blood levels approximately one hour after administration. Blood levels drop to one-half of the maximum in 3 to 5 hrs. and are entirely clear within 24 hrs. The compounds of this invention do not show evidence of N conjugation in total blood sulfa determination which certain sulfas of other classes show. The short-lived activity of the compounds of the present invention is advantageous since it is known that long-acting sulfas are especially liable to produce a hypersensitivity reaction (Brit. Med. J., Dec. 5, 1964, page 1410). They are devoid of hypoplycemic action which certain other classes of sulfas have. They do not have any effect on the cardiovascular system of the anesthetized dog when administered at mg./kg. intravenously.

As a result of advantageous pharmacological properties, such as high lipid solubility, low toxicity, lack of hypoglycemic activity, rapid absorption, and short duration, these novel N-methyl-alkanesulfonamido sulfa drugs are useful improvements in the therapeutic treatment of bacterial infections.

The compounds of this invention are administered to mammals in dosage of from 5 to 225 mg./ kg. body weight per day by the oral or the parenteral routes. They may be conveniently formulated into dosage units such as tablets or capsules containing from about 50 to 1500 mg. of the active ingredient. The compounds may be formulated into 3,567,7l5 Patented Mar. 2, 1971 various liquid preparations such as elixirs, suspensions and solutions adapted for parenteral use or for oral pediatric use. They may also be administered in combination with other drugs, such as the antibiotics, penicillins, the tetracyclines or with anti-inflammatory or antipyretic drugs, etc.

Particularly preferred embodiments of this invention are N methyl-N-(6-sulfanilamido-4-pyrimidinyl)butanesulfonamide, N-methyl-N- (2-sulfanilamido-S-pyrimidinyl) butanesulfonamide, and pharmaceutically acceptable metal salts thereof. These preferred compounds have high lipophilic properties and are rapidly absorbed from the stomach providing maximum blood levels in approximately 1 hr. Within 3 to 5 hrs. blood levels of the preferred embodiments drop to one-half the maximum and are completely cleared in 24 hrs. which is advantageous in con trolling hypersensitivity should it be encountered with the present compounds.

The substances of Formula I are prepared as illustrated by Method 1. In Formulas III and IV R has the meaning previously defined.

Method 1.

Cl Cl Cl N S 02R Step 1 I Step 2 N N 0113 Formula I Formula III Formula IV Step 1 involves the displacement of a single chlorine atom of the 4,6-dichloropyrimidine starting material of Formula III by reaction with an alkali metal salt of an N-methylalkanesulfonamide to provide the N-rnethyl-N- (6-chloro-4-pyrimidinyl)alkanesulfonamides of Formula IV. The process of Step 1 is carried out at low to moderate temperatures, e.g. 0-100" 0., and is greatly facilitated by the use of diluents comprising inert organic liquids. These include protolytic as well as aprotic solvents. Dimethylsulfoxide is particularly useful as a reaction medium. Reagents suitable for the formation of the alkali metal salts of N-methylalkane-sulfonamide include potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium amide, lithium amide, sodium hydride, butyl lithium, phenyl lithium, potassium tert.-butoxide and the like.

The sulfanilamido pyrimidines of Formula I are obtained by displacement of the chlorine atom of Formula IV as shown in Step 2 of Method 1. This step may be conveniently carried out by the reaction of compounds of Formula IV with two equivalents of sodium or other alkali metal sulfanilamides in dimethylsulfoxide at temperatures somewhat above 50 C. The reaction of the sodium sulfanilamide with the mono chloro substituted pyrimidine of Formula IV is carried out at temperatures ranging from about 50 C. to C. for periods of from about 2 hrs. to several days or more. The substances of Formula I can also be obtained by fusion of an alkali metal salt of the sulfanilamide with compounds of Formula IV at temperatures of approximately 200 C. preferably with a copper-bronze catalyst employing an inorganic base (e.g. potassium carbonate).

The substances of Formula II are prepared according to Method 2 shown in the following equations; R is as previously defined.

Method 2 N AONH Q4102 Step Formula V N AcNH NH2 Formula VI N AcNH- NHs 02R Step 3 Formula VII N AoNll -NS 02R 4 N on.

Formula VIII Formula IX Formula X Formula II In carrying out steps 1, 2 and 3, the amino group in 2-amino-S-nitropyrimidine is protected by acylation with acetic acid or acetic anhydride. The process of Step 1 involves reducing the nitro to the amino of Formula VI followed by Step 2 involving reaction with an alkanesulfonyl halide or an alkanesulfonic anhydride of the formula RSO X wherein X is chlorine bromine, iodine or R80 to produce compounds of Formula VII. Sulfonylation of compounds of Formula VI in Step 2 is carried out under conventional conditions for the preparation of sulfonamides, preferably in pyridine which satisfactorily serves as an acid scavenger as well as a diluent. Other acid scavengers such as organic bases, e.g. triethylamine, as well as inorganic bases such as sodium hydroxide or potassium hydroxide may be used in inert solvents. Temperatures of from -100 C. may be employed.

The process of Step 3 is conveniently carried out by forming metal salts of compounds of Formula VII employing aforementioned metal salt forming reagents and then alkylating with a methyl halide. A convenient alkylating agent is methyl iodide. Other suitable alkylating agents are dimethyl sulfate, trimethylphosphate, etc. Sodium salts of Formula VII substrates are preferred in the ordinary case due to the ease of preparation and reactivity with the alkylating reagent. Step 3 is carried out in an inert diluent, preferably dimethylformamide.

In Step 4, the protective acetyl group is removed by hydrolysis of the compounds of Formula VIII employing aqueous bases such as sodium or potassium hydroxide. Alternately, other standard methods of hydrolysis, such as the use of alkali bases in polar organic liquids can be employed.

The process of Step 5 is carried out by treating the N-methyl(2-amino-5 pyrimidinyl)alkanesulfonamides of Formula IX with para-nitrobenzenesulfonyl halide or anhydride in a solvent such as pyridine at temperatures from about 0-100 C. Solvents and reaction conditions described in obtaining compounds of Formula VII are also applicable to this step.

The compounds of Formula II are obtained from the nitrobenzene-sulfonamides (Formula X) by reduction of the nitro group shown as Step 6. The reduction reaction is preferably carried out catalytically employing a platinum oxide catalyst although reduction catalysts such as palladium and Raney nickel may be employed as well as numerous chemical reduction methods such as zinc- HCl, iron-HCl hydrazine-Raney nickel, sodium hydrogen sulfite, etc.

The following procedures illustrate the preparation of the intermediates and specific embodiments of the present invention. Typical pharmaceutical formulations are illustrated as well as methods of treating bacterial infections.

4 PROCEDURE 1 Preparation of N-methylalkanesulfonamides An n-alkanesulfonyl chloride (0.5 mole) dissolved in 500 ml. of anhydrous ethyl ether is added dropwise with stirring at 0 C. to a solution of methylamine (1.5 mole) in 500 ml. of anhydrous ether. The reaction is stirred overnight, filtered from precipitated methylamine hydrochloride, and the filter cake washed with 400 ml. of ethyl ether. The filtrate and ether wash are combined, stripped of solvent under reduced pressure, and the residual N- methylalkanesulfonamide is purified by distillation.

The above method is used to prepare N-methyl-npropanesulfonamide, N-methyl n butanesulfonamide, and N-methyl-n-pentanesulfonamide.

PROCEDURE 2 N-(6-chloro-4-pyrimidinyl) -N-methylpropanesulfonamide The potassium salt of N-methylpropanesulfonamide is prepared by adding 6.6 g. (0.1 mole) of KOH pellets to 13.7 g. (0.1 mole) of N-methylpropanesulfonamide in 50 ml. of methyl alcohol and then removing the solvent under reduced pressure (10 mm.) at 80 C. The residual potassium salt of N-methylpropanesulfonamide is taken up in 20 m1. of dimethylsulfoxide and added slowly to 14.9 g. (0.1 mole) of 4,6-dichloropyrimidine [Hull, J. Chem. Soc. 2214 (1951)] in 30 ml. of dimethylsulfoxide with stirring. The temperature of the reaction mixture increases spontaneously as the potassium salt is added. After stirring for 2.5 hr. the reaction mixture is poured into 1 liter of ice water providing a precipitate which is collected; weight 19.5 g. (78%), M.P. 6364 C. crystallization of this material from isopropyl etherpetroleum ether (B.P. 3060 C.) provides 15.2 g. (61%) of pure product, M.P. 63.064.5 C, (corr.).

AnaIysis.Calcd. for C H ClN O S (percent): C, 38.47; H, 4.85; N, 16.83. Found (percent): C, 38.49; H, 4.80; N, 16.90.

PROCEDURE 3 N- 6-chloro-4-pyrimidinyl -N-methylbutanesulfonamide This substance is prepared according to Procedure 2 from 4,6-dichloropyrimidine and N-methylbutanesulfonamide. The product is purified by crystallization from acetone-cyclohexane, M.P. 61.563.5 C. (corr.).

Analysis.Calcd. for C H ClN O S (percent): C, 40.99; H, 5.35; N, 15.93. Found (percent): C, 41.00; H, 5.34; N, 15.67.

PROCEDURE 4 N-(6-chloro-4-pyrimidinyl -N-methylpentanesulfonamide This product is prepared from 4,6-dichloropyrimidine and N-methylpentanesulfonamide according to Procedure 2.

PROCEDURE 5 N-methyl-N- 6-sulfanilamido-4-pyrimidinyl alkanesulfonamides A mixture of 1 mole of N-methyl-N-(6-chloro-4- pyrimidinyl)alkanesulfonamide, 2 moles of sodium sulfanilamide and dimethylsulfoxide equal to three times the combined weight of the starting materials is heated at C. for 6 hr. The resulting suspension is diluted with 20 volumes of ice water and chilled overnight at 510 C. The by-product sulfanilamide is removed by filtration and the filtrate is acidified with glacial acetic B.P. 105 C./0.1 mm. Hg, no 1.4523 (02% yield). Analysis-Calm. for CAI'IIINOQS (percent) C, 35.01; 8.08; N, 10.21. Found (percent) Q3524; H, 8.00; N, 10.05). -'B.P. 11S C./0.3 mm. Hg, m) 1.4548 (99% yield). Analysis.Calcd. for CsHmNOzS (percent): C. 39.71; H, 8.66; S, 21.20. Found (percent) Q4004; H, 8.06; S, 20.87.

acid. The product which precipitates is collected, airdried overnight and purified by crystallization.

Products which can be obtained by the above procedure and representative yields, melting points, and crystallization solvents are indicated below.

N-methyl-N-(G sulfanilamido-4-pyrimidinyl)propanesulfonamide, 54%, M.P. 205.5206.0 C. (corn) (from acetonitrile) Analysis.--Calcd. for C H N O S (percent): C, 43.62; H, 4.97; N, 18.17. Found (percent): C, 43.40; H, 4.98; N, 18.26.

Infrared absorption maxima (0.5% in KBr pellet): 2.90, 3.00, 6.30, 7.20, 7.40, 8.70, 9.15, 10.10, 10.25, 11.00, 12.00, 14.80 microns.

N-methyl-N-(6 sulfanilamido-4-pyrimidinyl)propanesulfonamide, 50%, M.P. 162.5163.0 C. (corn) (from absolute ethyl alcohol-isopropyl ether).

Analysis.Calcd. for C H N O S (percent): C, 45.10; H, 5.30; N, 17.53. Found (percent): C, 45.10; H, 5.29; N, 17.49.

Infrared absorption maxima (0.5% in KBr pellet): 2.90, 3.00, 6.30, 7.20, 7.40, 8.70, 9.20, 10.10, 10.30, 11.00, 12.00, 14.75 microns.

N-methyl-N-(6 sulfanilamido-4-pyrimidinyl)pentanesulfonamide.

PROCEDURE 6 N-methyl-N-(2-sulfanilamido-S-pyrimidinyl)- butanesulfonamide Z-acetamido-5-nitropyrimidine (2.7 g., 15 mmole) prepared from 2-amino-5-nitropyrimidine as described in Roblin et al., J. Am. Chem. Soc., 64, 567 (1942), is reduced on a Parr Apparatus in 150 ml. of methanol employing 0.3 g. of 20% palladium-on-carbon catalyst. The hydrogen uptake stops at the theoretical value (45 mmole) in 2.5 hr. The catalyst is collected, the filtrate evaporated to dryness at 80 C./ 10 mm. Hg and the residue immediately taken up in 35 ml. of dry pyridine. Butanesulfonyl chloride 2.4 g., 15 mmole) is added in a period of l min. to the pyridine solution of Z-acetamido- S-aminopyrimidine at room temperature. The stirred pyridine solution is warmed to 5055 C. for 5 min. and then stirred for an additional hour at room temperature. Pyridine is removed at 80 C. under reduced pressure (10 mm.) and the syrupy residue taken up in 150 ml. of water. The aqueous mixture is made acid to pH 2 with l N hydrochloric acid and chilled. The product which precipitates is collected and dried; yield 3. g. (M.P. 181183 C.). Crystallization from 95% ethyl alcohol provides 2.6 g. (64%) of analytically pure N-(2- acetamido-S-pyrimidinyl)butanesulfonamide, M.P. 184- 185.5 C. (corr.).

Analysis.Calcd. for C H N S (percent): C, 44.10; H, 5.92; N, 20.57. Found (percent): C, 44.29; H, 5.86; N, 20.17.

N-(Z-acetamido pyrimidinyl)butanesulfonamide (2.4 g., 8.8 mmole) is suspended in ml. of dimethylformamide and 0.4 g. (8.9 mmole) of 53% sodium hydride in oil added. To insure complete conversion to the sodium salt of the sulfonamide, the mixture is stirred for 30 min. at 30 C. Methyl iodide (1.42 g., 10 mmole) is added in one portion to the reaction mixture and stirring is continued for 30 min. at 50 C. Dilution of the cooled reaction mixture with 80 ml. of ice water precipitates 2.4 g. of white solid (M.P. 147-150 C.). Crystallization of this product first from 2-propanol-acetonitrile and then from ethyl acetate provides 1.3 g. (52%) of analytically pure N-(2-acetamido 5 pyrimidinyl)-N- methylbutanesulfonamide, M.P. l54155.5 C. (corr.).

Analysis.-Calcd. for C H N O S (percent): C, 46.14; H, 6.34; N, 19.57. 'Found (percent): C, 46.37; H, 6.04; N, 19.76.

Heating a suspension of 1.1 g. (3.84 mmole) of N- (Z-acetamido 5-pyrimidinyl) N-methylbutanesulfonamide in 10 ml. of 1 N sodium hydroxide solution and 1 ml. of 2-propanol at -95 C. for 30 min. hydrolyzes the 2-acetamido moiety and provides N-(Z-amino 5- pyrimidinyl) N-methylbutanesulfonamide. The deacetylated product is isolated by cooling the mixture in ice and collecting the precipitated product; yield 0.9 g., M.P. l20122 C. Crystallization from 2-propanol affords 0.5 g. (53%) of analytically pure product, M.P. 121122 C. (corr.).

Analysis.-Calcd. for C H N O S (percent): C, 44.24; H, 6.60; N, 22.93. Found (percent): C, 44.46; H, 6.46; N, 23.13.

p-Nitrobenzenesulfonyl chloride (2.21 g., 10 mmole) is added in 1 min. to 2.44 g., (10 mmole) of N-(Z-arnino- S-pyrimidinyl) N methylbutanesulfonamide dissolved in 25 ml. of pyridine at 30 C. The mixture is stirred for 18 hrs. at 30 C. (lengthening the stirring period gives improved yields) and the pyridine solvent is then stripped off at 70 C. under reduced pressure (20 mm.). The residue is taken up in ml. of water which contains sufiicient ammonium hydroxide to effect solution. The solution is stirred with diatomaceous earth, filtered and the filtrate treated with activated charcoal. The charcoal is collected and the filtrate acidified with concentrated hydrochloric acid to a pH of 2, providing 1.5 g. of a tan precipitate, M.P. 182185 C. Crystallization of the solid first from acetonitrile and then from absolute ethyl alcohol yields N-methyl-N-(2-nitrobenzenesulfonamido- S-pyrimidinyl)butanesulfonamide, weight 0.85 g. (20%), M.P. 194-195 C. (corr.).

Analysis.Calcd. for C H N O S (percent): C, 41.95; H, 4.46; N, 16.31. Found (percent): C, 41.74; H, 4.48; N, 16.42.

A suspension of 12.15 g. (28.3 mmole) of N-methyl- N (2 p nitrobenzenesulfonamido-5-pyrimidinyl)butanesulfonamide in 1.2 liter of absolute methanol containing 1 g. of 84% platinum oxide hydrogenation catalyst is reduced at one atmosphere pressure at 30 C. The calculated quantity of hydrogen is absorbed within 4 hrs. and the product is then isolated by separation of the catalyst by filtration and evaporating the filtrate to dryness under vacuum. The white amorphous residue crystallized first from 2-propanol and then from benzene-acetonitrile yields 7.3 g. (65%) of analytically pure N-methyl N-(2-sulfanilamido 5-pyrimidinyl)butanesulfonamide M.P. 168.5-170.5 C. (corr.).

Analysis.Calcd. for C H N O S (percent): C, 45.10; H, 5.30; N, 17.53. Found (percent): C, 45.21; H, 5.39; N, 17.57.

Infrared absorption maxima (0.5% in KBr pellet): 2.90, 3.00, 6.25, 6.35, 6.90, 7.60, 8.75, 9.30, 10.75, 11.50, 12.70, 14.75 microns.

PROCEDURE 7 N-methyl-N-(2-sulfani1amido-5-pyrimidinyl) -propanesulfonamide This material is prepared according to Procedure 6 beginning with the sulfonylation of 2-acetamido-5-aminopyrimidine with propanesulfonyl chloride.

PROCEDURE 8 N-methyl-N- (2-sulfanilamido-S-pyrimidinyl -pentanesulfonamide This substance is prepared according to Procedure 6 beginning with the sulfonylation of 2-acetamido-5-aminopyrimidine with pentanesulfonyl chloride.

PROCEDURE 9 Chemotherapeutic activity The in vivo antibacterial activity of the test drug is determined in mice against infection produced by Streptococcus pyogenes C-203. Groups of five male albino mice, weighing 1824 g., are infected by intra-abdominal injections of a mucin solution containing 1.15 X 10 Streptococci. Treatment consists of three intra-abdominal injections of solutions of the sulfonamide suspended in 0.5% Methocel 400 according to its body weight at peroads of 1, 6, and 24 hrs. after infection. The mice are observed for 2 weeks and deaths are recorded at daily intervals. The therapeutic activity for each test drug was evaluated according to the dose-effect method of Litchfield and Wilcoxon, J. Pharmacol. Exptl. Therap. 96, 99 (1949).

The following median curative dose for representative N -1 rnethylalkanesulfanilamido pyrimidines is illustrative of their chemotherapeutic actions.

Compound name: CD mg./kg. N-methyl-N-(6-sulfanilamido 4 pyrimidinyl) butanesulfonamide N-methyl-N-(6-sulfanilamido 4 pyrimidinyl) propanesulfonamide 280 N-methyl-N-(2-sulfanilamido 5 pyrimidinyl) butanesulfonamide PROCEDURE l0 Dosage unit The preferred substances of Formula I and Formula II are prepared in a dosage unit form according to the following example.

30 G. N methyl-N-(6-sulfanilamido 4 pyrimidinyl)- butanesulfonamide 400 Polyvinylpyrrolidone 34 Crystalline cellulose 200 Corn starch, USP 20 Stearic acid powder 12 Magnesium stearate 4 These materials are thoroughly blended dry and the batch then fed to a tabletting machine to provide 100 tablets each containing 400 mg. of N-methyl-N-(G-sulfanilamido-4-pyrimidinyl)butanesulfonamide.

What is claimed is:

1. A compound selected from the group consisting of N CH:

References Cited UNITED STATES PATENTS 3,422,098 1/1969 Schmidt et a1. 260-23975 3,432,493 3/1969 Short 260239.75

HENRY R. IILES, Primary Examiner C. M. SHURKO, Assistant Examiner U.S. Cl. X.R. 424-229 UNITED s'm'rics m'ncw'r OFFICE CEE'EVE FICATEi, OF CORRECTION Patent No. 3,567 715 Dated March 2, 1.971

Inventor(s) AUBREY A. LARSEN, FREDERICK A. GRUNWALD and WILLIAM E. KREIGHBAUM It is certified that error appears in the above-identified pate and that said Letters Patent are hereby corrected as shown below:

Col. 1, Line 23 "alkanesulfonamide" should be alkanesulfonamides Col. 1, Line 68 "dosage" should be dosages Col. 5, Line 40 After "chloride" insert Col. 6, Line 28 After "(2-" insert p Col. 7, Lines 4-5 "peroads" should be periods Col. 7, Line 11 After "N-" delete l Claim 1 "SO HH' should be SO NH Signed and sealed this lhth day of December 1 971 (SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Acting Commissioner of Batem 

